We propose a longitudinal study of biochemical, microstructural, functional and behavioral changes in mice overexpressing mutant human amyloid precursor protein genes in order to detect early changes that are critical to cognitive decline. The study will examine heterozygous Tg2576 and PDAPP mice at pre-determined ages, from a very young age over their entire lifespan. Non-transgenic littermates will be used as controls. The integrity of the hippocampal subfields CA1 and CA3, dentate gyrus, and connected cortical and subcortical structures of the hippocampal circuit is crucial for memory and learning. We hypothesize subtle changes occur in the cytoarchitecture of the neuronal assemblies in the hippocampal circuit as a result of the changing nature of A[unreadable]. Structural changes precede amyloid deposition in the developing A[unreadable] pathology. Microstructural changes, reflected in water self-diffusion characteristics, will be measured using in vivo diffusion tensor MR imaging with high spatial resolution. Fractional anisotropy will be calculated for the regions of interest. Morphometric analysis will be carried out to investigate the cytological basis for changes in diffusion anisotropy. Detergent soluble and detergent insoluble A[unreadable] will be measured to follow the course of A[unreadable] pathology. In preliminary experiments on Tg2576 mice, we have found significant reduction in fractional anisotropy in dentate gyrus and CA3 subfield of 24-week old mice relative to control mice, one of the earliest changes observed in the hippocampus in APP transgenic mice. At 12 weeks of age, transgenic and control mice exhibited similar diffusion characteristics. We further hypothesize that A[unreadable] induced microstructural changes to the hippocampal regions are likely to compromise hippocampal function and in turn lead to deficits in behavior. Disruption in the function of the hippocampal circuit will be measured by recording field oscillations at the theta band in the area over the dorsal hippocampus during locomotion in an open field. The ability of the mice to perform hippocampally-dependent tasks will be measured using the Morris water maze task. The proposed study will identify the hippocampal subdivisions and related cortical and subcortical structures that are affected early by the developing A[unreadable] pathology. Such information could be useful for developing therapeutic strategies for the treatment of AD. The longitudinal design of the research plan will minimize individual differences and cohort effects that may affect cross-sectional studies.